Pulmonary Disorders II

Intermediate/High- strata

Add a parenteral prostacyclin—or—

ii.

Add an activin-signaling inhibitor (N Engl J Med. 2023;388(16):1478-1490).

Add a parenteral prostacyclin agent (first choice if not already receiving)—or—

ii.

Add an activin-signaling inhibitor.

Persistent intermediate-high or high-risk

Refer for lung transplantation if on maximal drug therapy with: parenteral prostacyclin agent,

endothelin receptor antagonist (ERA), PDE5i, sGC, activin-signaling inhibitor

ERAs (Table 6)

Competitively block the action of ET-1 from acting on two types of ET receptors: ETa and ETb. This

blockade prevents endogenous ET-1 from its normal actions:

ETa = vasoconstriction and cell proliferation

ii.

ETb = vasodilation and antiproliferation of pulmonary endothelial cells

Minimal place in therapy for initiation in critically ill patients

Inhibit PDE-5, which prevents the breakdown of cyclic guanosine monophosphate in pulmonary

vascular smooth muscle. Increased cyclic guanosine monophosphate potentiates pulmonary

vascular smooth muscle and vasodilation of the pulmonary vascular bed.

Intravenous formulation of sildenafil is available for patients who temporarily cannot ingest tablets;

however, this formulation is limited by its hemodynamic effects.

Bosentan

Ambrisentan

Macitentan

Receptor affinity

Blocks ETa and ETb

Preferentially blocks ETa

Blocks ETa and ETb

Half-life (hr)

Approved dose

62.5–125 mg BID

5–10 mg daily

10 mg daily

Adverse effects

Hepatotoxicity (bosentan only), peripheral edema, anemia, contraindicated during

pregnancy (As of April 4, 2025, Bosentan is the only ERA with a REMS programs)

Drug

interactions

Glyburide (contraindicated)

and cyclosporine (contra-

indicated), CYP2C9 and

CYP3A4 inhibitors and

inducers, hormonal contra-

ceptives, warfarin, sildenafil

and tadalafil

Caution with cyclosporine

(max ambrisentan dose is

5 mg daily)

CYP2C19 and strong CYP3A4

inhibitors and inducers

BID = twice daily; ET = endothelin; REMS = risk evaluation and mitigation strategies.

Information from: Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834-44;

Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022;43:3618-731.